Antidepressant naphthyloxy piperidino and pyrrolidino propanol ethers

ABSTRACT

Disclosed herein are compounds of the formula ##STR1## in which Ar is phenyl or 1-naphthyl; R 1  is hydrogen or lower alkyl; and R 2  and R 3  together with the nitrogen atom to which they are joined form a heterocyclic amine radical selected from the group consisting of 1-pyrrolidinyl, piperidino, morpholino and 4-(lower alkyl)-1-piperazinyl. The compounds are antidepressant agents and methods for their preparation and use also are disclosed.

This is a division of application Ser. No. 687,851, filed May 19, 1976,now U.S. Pat. No. 4,060,613, issued Nov. 29, 1977.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to aryloxy aminopropanols having antidepressantactivity, to a process for their preparation, to intermediates used forthe process, and to pharmaceutical compositions and a method of use forthese aryloxy aminopropanols.

(B) Prior Art

During the last few decades, psychotherapy has become more effective dueto the adjunct use of new central nervous system agents, in particular,the use of tranquilizers and antidepressants. As a consequence thedevelopment of new and useful agents for psychotherapy has beendiligently pursued, and the finding of a potent, well tolerated agent isnoteworthy indeed.

The present invention discloses a group of antidepressant agents havingthese attributes. The agents are aryloxy aminopropanols. A number ofaryloxy aminopropanols are known to possess pharmacologic properties;for example, 1-isopropylamino-3-(1-naphthyloxy)-2-propanol, J. W. Black,et al., Lancet, 1, 1080(1964), a potent β-blocking agent, and a group ofalkyl ethers of 3-amino-1-phenoxy-2-propanol derivatives, V. Dauksas andL. Pikunaite, Zh. Vses. Khim. Obshchestva im. D. I. Mendeleeva, 9, 352(1964); Chem. Abstr., 61, 6942c(1964) having a stimulating effect on thecentral nervous system. The compounds of the present invention aredistinguished readily from the prior art compounds by having a differentstructural relationship with respect to the substituents. A compound,2-isopropylamino-3-(1-naphthyloxy)-1-propanol, having the samestructural relationship respecting the substituents has been reported,R. Howe, J. Med. Chem., 13 398 (1970). The compound was devoid ofβ-receptor blocking activity in the only pharmacological testingreported therefor. When tested for antidepressant activity according tomethods described herein, the compound was found to be devoid of or tohave marginal activity.

SUMMARY OF THE INVENTION

The compounds of this invention are represented by formula 1 ##STR2## inwhich Ar is phenyl or 1-naphthyl; R¹ is hydrogen, lower alkyl; and R²and R³ together with the nitrogen atom to which they are joined form aheterocyclic amine radical selected from the group consisting of1-pyrrolidinyl, piperidino, morpholino and 4-(loweralkyl)-1-piperazinyl; or a therapeutically acceptable salt thereof.

Pharmaceutical compositions comprising the compound of formula 1, or atherapeutically acceptable acid addition salt thereof, and apharmaceutically acceptable carrier are included within the scope ofthis invention.

Also included is a method for alleviating the symptoms of depression inmammals by administering to said animals an effective dose of thecompound of formula 1, or a therapeutically acceptable salt thereof.

DETAILS OF THE INVENTION

The term "lower alkyl" as used herein contemplates straight chain alkylradicals containing from one to six carbon atoms and branched chainalkyl radicals containing three to four carbon atoms and includesmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl and the like.

The term "lower alkanoic acid" as used herein contemplates both straightand branched chain alkanoic acids containing from one to six carbonatoms and includes formic, acetic, propionic, tert-butanoic, pentanoic,hexanoic acids and the like.

The compounds of formula 1 are capable of forming acid addition saltswith therapeutically acceptable acids. Such acid addition salts areincluded within the scope of this invention.

The acid addition salts are prepared by reacting the corresponding baseform of the compound of formula 1 with at least one equivalent, orpreferably with an excess of the appropriate acid in an organic solvent,for example, ether or an ethanol-ether mixture. These salts, whenadministered to mammals, possess the same pharmacologic activities asthe corresponding bases. For many purposes it is preferable toadminister the salts rather than the base compounds. Among the acidaddition salts suitable for this purpose are salts such as the sulfate,phosphate, lactate, tartrate, maleate, citrate, hydrobromide andhydrochloride. Both the base compounds and the salts have the distinctadvantage of possessing a relatively low order of toxicity.

Also included in this invention are the stereochemical isomers of thecompounds of formula 1 which result from asymmetric centers containedtherein.

Individual optical isomers, which might be separated by fractionalcrystallization of the diastereoisomeric salts thereof, for instance,salts with d- or l-tartaric acid or D-(+)-α-bromocamphor sulfonic acid,are also included.

The antidepressant activity of the compounds of formula 1 and their acidaddition salts with pharmaceutically acceptable acids is demonstrated instandard pharmacologic tests such as, for example, the tests describedby F. Hafliger and V. Burckhart in "Psychopharmacological Agents", M.Gordon, Ed., Academic Press, New York and London, 1964, pp. 75-83.

More specifically, as noted in the latter reference the antidepressantproperties of a compound may be demonstrated by its capacity toantagonize the depressant effects of reserpine. Furthermore, it is welldocumented that reserpine in animals produces a model depression whichcan be used for detecting antidepressant properties. Accordingly, thecompounds of the present invention antagonize reserpine effects in miceat doses ranging from about 1 to 100 mg/kg.

The antidepressant activity of the compounds of formula 1 is alsodemonstrated by the method of D. F. Bogdanski, et al., J. Pharmacol.Exp. Ther., 122, 182 (1958) which measures the effect of the testcompound on the 5-hydroxytryptophan(5-HTP)-induced syndrome. In thistest the degree of intensity of the 5-HTP-induced syndrome, i.e.extension and abduction of hindlimbs, lordosis, tremors, head movementsand excitation, following the administration of the test compound toSwiss albino mice, is indicated by a scale ranging from +1 (weak effect)to +4 (very strong effect). A positive score in the test is indicativeof antidepressant agents having desirable mood elevation properties, seeA. Carlsson, et al., Eur. J. Pharmacol., 5, 357 (1969). Several of thepreferred compounds, for example,1-{[1-(ethoxymethyl)-2-(1-naphthyloxy)]ethyl}piperidine hydrochloride,produces a significant effect (+1 to +3) on the 5-HTP-induced syndromeat doses of 6.25 to 25 mg/kg, i.p., when administered to mice (five pergroup) 30 minutes prior to the 5-HTP injection (300 mg/kg, i.p.).

The following table illustrates further a comparative study of1-{[1-(ethoxymethyl)-2-(1-naphthyloxy)]ethyl}piperidine hydrochloride,imipramine hydrochloride and desimipramine hydrochloride in thepotentiation of the 5-HTP-syndrome test.

    ______________________________________                                        Compound       Dose(mg/kg,i.p.)                                                                           Behavioral Score                                  ______________________________________                                        saline         --           0                                                 1-{[1-(ethoxymethyl)-2-                                                                      25           +3                                                (1-naphthyloxy)]ethyl}-                                                                      12.5         +1                                                piperidine hydrochloride                                                                     6.25         +1                                                (Example 4)                                                                   imipramine hydrochloride                                                                     25           +3                                                               12.5         +2                                                               6.25         +1                                                desimipramine  25           +1                                                hydrochloride                                                                 ______________________________________                                    

When the compounds of formula 1 were used as antidepressants in mammals,e.g. rats and mice, they may be used alone or in combination withpharmacologically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard biological practice. For example,they are administered orally in solid form containing such excipients asstarch, milk sugar, certain types of clay and so forth. They may also beadministered orally in the form of solutions or they may be injectedparenterally. For parenteral administration they may be used in the formof a sterile solution containing other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The dosage of the present invention therapeutic agents will vary withthe form of administration and the particular compound chosen.Furthermore, it will vary with the particular host under treatment.Generally, treatment is initiated with small dosages substantially lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. In general, the compounds of this inventionare most desirably administered at a concentration level that willgenerally afford effective results without causing any harmful ordeleterious side effects and preferably at a level that is in a range offrom about 0.1 mg to about 100 mg/kg per day, although as aforementionedvariations will occur. However, a dosage level that is in the range offrom about 0.5 mg to about 50 mg/kg per day is most desirably employedin order to achieve effective results.

The compounds of formula 1 in which R¹ is hydrogen an Ar, R² and R³ areas defined herein are prepared by a process represented by the followingflow diagram. ##STR3##

The starting material of formula 2 in which Ar is phenyl,1,2-epoxy-3-phenoxy-propane, is described by W. Bradley, J. Forrest andO. Stephenson, J. Chem. Soc., 1589 (1959) and the starting material offormula 2 in which Ar is 1-naphthyl, 1,2-epoxy-3-(1-naphthoxy)propane,is described by A. F. Crowther and L. H. Smith, J. Med. Chem., 11, 1009(1968).

With reference to the flow diagram, the compounds of formula 1 in whichR¹ is hydrogen and Ar, R² and R³ are as defined herein are prepared by aprocess comprising: reacting the starting material of formula 2 with anamine of formula NHR² R³ in which R² and R³ are as defined herein toobtain the β-hydroxypropylamine of formula 3 in which Ar, R² and R³ areas defined herein; reacting the last-named compound withp-toluenesulfonic acid chloride or thionyl chloride to obtain thecorresponding β-chloropropylamine of formula 4, reacting the lattercompound with a lower alkanoic acid of formula R⁴ COOH in which R⁴ ishydrogen or lower alkyl in the presence of an alkali salt of the loweralkanoic acid to obtain the compound of formula 5 in which Ar, R², R³and R⁴ are as defined herein, and hydrolyzing the latter compound withan acid or a base to obtain the corresponding compound of formula 1 inwhich R¹ is hydrogen.

More specifically, convenient conditions for converting the startingmaterial of formula 2 to the hydroxypropylamine of formula 3 includereacting the starting material of formula 2 with about one molarequivalent of the appropriate amine of formula NHR² R³ in an inertsolvent, for example, diethyl ether, methanol or tetrahydrofuran, at 0°to 40° C. for ten minutes to four hours.

Subsequent transformation of the hydroxypropylamine of formula 3 to thecorresponding β-chloropropylamine is conveniently effected by reactingin an inert organic solvent the hydroxypropylamine with about one molarequivalent of tosyl chloride or thionyl chloride, tosyl chloride beingpreferred, at 10° to 80° C. for two to 24 hours. The reaction ispreferably carried out in the presence of an excess of an organic base,for example, triethylamine or pyridine. Suitable inert organic solventsinclude benzene, diethyl ether or tetrahydrofuran.

Thereafter the β-chloropropylamine of formula 4 is converted to thecompound of formula 5 under mildly acidic condition using an excess of alower alkanoic acid, preferably acetic acid, in the presence of one toten molar equivalents of an alkali salt of the lower alkanoic acid,preferably sodium or potassium acetate. It has been found convenient touse the lower alkanoic acid as a solvent for this reaction, andtemperatures and times ranging from 10° to 100° C. and one to six hours,respectively. It should be noted that this reaction involves arearrangement of the amino radical (NR² R³).

Subsequent hydrolysis of the compound of formula 5 to the correspondingcompound of formula 1 in which R¹ is hydrogen is effected using an acidor a base as the hydrolysis agent. Hydrolysis is preferably effectedwith a base. For the basic hydrolysis a preferred embodiment involvessubjecting the compound of formula 5 to the action of a strong base, forexample, sodium or potassium hydroxide, in the presence of sufficientwater to effect hydrolysis. The hydrolysis is performed using a suitablesolvent, for example, methanol or ethanol and the reaction mixture ismaintained at a temperature of from 25° C. to the reflux temperatureuntil hydrolysis occurs. Usually from ten minutes to six hours issufficient for this hydrolysis. The reaction mixture is extracted withan organic solvent, for example diethyl ether, and the extract worked upin the usual manner to afford the compound of formula 1 in which R¹ ishydrogen.

The compounds of formula 1 in which R¹ is lower alkyl and Ar, R² and R³are as defined herein are prepared by reacting the above-mentionedβ-chloropropylamine of formula 4 with an appropriate alcohol of formulaR⁵ OH in which R⁵ is lower alkyl in the presence of sodium or potassiumalkoxide in which the alkyl portion thereof corresponds to the loweralkyl of R⁵, preferably one to ten moles. This reaction proceeds readilywithin about 15 minutes to two hours at 20° to 80° C. using an excess ofthe alcohol as a reaction medium. When benzyl alcohol is used as thealcohol together with sodium or potassium phenylmethoxide in thisreaction, the corresponding benzyl ether is obtained.

The following examples illustrate further this invention.

EXAMPLE 1 3-(1-Pyrrolidinyl)-1-(1-naphthyloxy)-2-propanol (3;Ar=1-naphthyl and NR² R³ =1-pyrrolidinyl)

A solution of 1,2-epoxy-3-(1-naphthyloxy)propane (62.0 g) and the amineof formula NHR² R³, pyrrolidine (23.5 g), in methanol (250 ml) is heatedat reflux for two hours. The reaction mixture is concentrated todryness. The oily residue is crystallized from chloroform and diethylether by the addition of hexane to give the title compound, mp 68°-70°C.

In the same manner but replacing pyrrolidine with an equivalent amountof piperidine, morpholine or N-methylpiperazine,

3-piperidino-1-(1-naphthyloxy)-2-propanol, γ_(max) ^(nujol) 3250 and2655 cm⁻¹, (the corresponding hydrochloride of the latter compound hasmp 189°-190° C.)

3-morpholino-1-(1-naphthyloxy)-2-propanol, mp 68°-70° C., and

3-(4-methyl-1-piperazinyl)-1-(1-naphthyloxy)-2-propanol, mp 73°-74° C.

In the same manner but replacing 1,2-epoxy-3-(1-naphthyloxy)propane withan equivalent amount of 1,2-epoxy-3-phenoxy-propane and usingpyrrolidine, piperidine, morpholine, or 1-methylpiperidine as the amineof formula NHR² R³,

3-(1-pyrrolidinyl)-1-phenoxy-2-propanol,

3-piperidino-1-phenoxy-2-propanol, mp 52°-54° C.,

3-morpholino-1-phenoxy-2-propanol, and

3-(4-methyl-1-piperazinyl)-1-phenoxy-2-propanol, are obtained,respectively.

EXAMPLE 2 1-{[2-Chloro-3-(1-naphthyloxy)]propyl}pyrrolidine (4;Ar=1-naphthyl and NR² R³ =1-pyrrolidinyl)

A solution of 3-(1-pyrrolidinyl)-1-(1-naphthyloxy)-2-propanol (56 g),described in Example 1, and tosyl chloride (43 g) in benzene (500 ml) isheated at reflux for 18 hours. The mixture is cooled, washed with dilutesodium bicarbonate and extracted with dilute hydrochloric acid. Thedilute hydrochloric acid extract is washed with ether, rendered neutralwith dilute sodium hydroxide and extracted with chloroform (CHCl₃). TheCHCl₃ extract is dried and concentrated. The residue is subjected tochromatography using silica gel as the absorbent. Elution with diethylether-methanol (9:1) yields unchanged starting material. Subsequentelution with diethyl ether-methanol (7:3) yields the title compound.

In the same manner but replacing3-(1-pyrrolidinyl)-1-(1-naphthyloxy)-2-propanol with an equivalentamount of

3-piperidino-1-(1-naphthyloxy)-2-propanol,

3-morpholino-1-(1-naphthyloxy)-2-propanol,

3-(4-methyl-1-piperazinyl)-1-(1-naphthyloxy)-2-propanol,

3-(1-pyrrolidinyl)-1-phenoxy-2-propanol,

3-piperidino-1-phenoxy-2-propanol,

3-morpholino-1-phenoxy-2-propanol,

3-(1-piperazinyl)-1-phenoxy-2-propanol,

3-(4-methyl-1-piperazinyl)-1-phenoxy-2-propanol,

the following β-chloropropylamines of formula 4,

1-{[2-chloro-3-(1-naphthyloxyl)]propyl}piperidine, mp 45°-48° C.,

1-{[2-chloro-3-(1-naphthyloxy)]propyl}morpholine, bp 158°-160° C./0.02mm/Hg,

1-{[2-chloro-3-(1-naphthyloxy)]propyl}-4-methylpiperazine,

1-[(2-chloro-3-penoxy)propyl]pyrrolidine,

1-[(2-chloro-3-phenoxy)propyl]piperidine (reported by Dauksas andPikunaite, cited above),

1-[(2-chloro-3-phenoxy)propyl]morpholine,

1-[(2-chloro-3-phenoxy)propyl]piperazine, and

1-[(2-chloro-3-phenoxy)propyl]-4-methylpiperazine, are obtained,respectively.

EXAMPLE 3 2-Piperidino-3-(1-naphthyloxy)-1-propanol (1; Ar=1-naphthyl,R¹ =H and NR² R³ =piperidino)

A mixture of the compound of formula 4,1-{[2-chloro-3-(1-naphthyloxy)]propyl}piperidine (10.0 g), described inExample 2, and sodium acetate (5.4 g) in acetic acid (50 g) is heated atreflux for two hours. The mixture is cooled and ether added to themixture. The resulting solid is collected on a filter. The filtrate isconcentrated to dryness. The residue is dissolved in diethyl ether. Thesolution is washed with dilute NaHCO₃, dried and poured onto a column ofsilica gel. Elution with ethyl acetate-benzene (1:4) gives2-piperidino-3-(1-naphthyloxy)-2-propanol acetate (5; Ar=1-naphthyl, NR²R³ =piperidino and R⁴ =CH₃), γ_(max) ^(EtOH) 318 nm (ε=1640), 304 nm(ε=3130), 287 nm (ε=6360), 229 nm (ε=29,700), 213 nm (ε=42,900).(Continued elution with ethyl acetate-benzene (1:4) gives the positionalisomer, 1-piperidino-3-(1-naphthyloxy)-2-propanol acetate). Thehydrochloric acid addition salt of2-piperidino-3-(1-naphthyloxy)-1-propanol acetate has mp 151°-157° C.

The 2-piperidino-3-(1-naphthyloxy)-1-propanol acetate so obtained ishydrolyzed in the following manner:

A suspension of 2-piperidino-3-(1-naphthyloxy)-1-propanol acetate (6.4g), 15% KOH in methanol (10 ml), methanol (10 ml) and water (20 ml) isheated at reflux for one hour. The reaction mixture is concentrated todryness. The residue is taken up in diethyl ether. The ether extract iswashed with water and concentrated to give the title compound as an oil,γ_(max) ^(EtOH) 319 nm (ε=1780), 350 nm (ε=3330), 288 nm (ε=6340), 230nm (ε=30,600), 212 nm (ε=44,180).

The hydrochloric acid addition salt (hydrochloride) of the titlecompound has mp 165°-170° C., after recrystallization frommethanol-diethyl ether.

In the same manner but replacing1-{[2-chloro-3-(1-naphthyloxy)]propyl}piperidine with another compoundof formula 4, described in Example 2, other corresponding compounds offormula 1 in which R¹ is hydrogen are obtained. For instance,replacement with

1-{[2-chloro-3-(1-naphthyloxy)]propyl}pyrrolidine,

1-{[2-chloro-3-(1-naphthyloxy)]propyl}morpholine,

1-{[2-chloro-3-(1-naphthyloxy)]propyl}-4-methylpiperazine,

1-[(2-chloro-3-phenoxy)propyl]pyrrolidine,

1-[(2-chloro-3-phenoxy)propyl]piperidine,

1-[(2-chloro-3-phenoxy)propyl]morpholine, or

1-[(2-chloro-3-phenoxy)propyl]-4-methylpiperzine,

gives

2-(1-pyrrolidinyl)-3-(1-naphthyloxy)-1-propanol,

2-morpholino-3-(1-naphthyloxy)-1-propanol,

2-(4-methyl-1-piperazinyl)-3-(1-naphthyloxy)-1-propanol,

2-(1-pyrrolidinyl)-3-phenoxy-1-propanol,

2-piperazino-3-phenoxy-1-propanol,

2-morpholino-3-phenoxy-1-propanol, and

2-(4-methyl-1-piperazinyl)-3-phenoxy-1-propanol, respectively.

EXAMPLE 4 1-{[1-(Ethoxymethyl)-2-(1-naphthyloxy)]ethyl}piperidine (1;Ar=1-naphthyl, R¹ =C₂ H₅ and NR² R³ =piperidino)

The compound of formula4,1-{[2-chloro-3-(1-naphthyloxy)]propyl}piperidine (7.0 g), is added toa solution of sodium (0.54 g) in ethanol (70 ml), i.e. the alcohol offormula R⁵ OH in which R⁵ is ethyl. The mixture is heated at reflux forone hour and cooled. Precipitated sodium chloride is collected on afilter and the filtrate is evaporated to yield an oil. The oil issubjected to chromatography on silica gel. Elution with diethylether-hexane (1:1) gives the title compound, γ_(max) ^(EtOH) 319 nm(ε=1710), 304 nm (ε=3290), 289 nm (ε=6400), 223 nm (ε=31,100), 212 nm(ε=44,300).

The corresponding hydrochloric acid addition salt of the title compoundhas mp 151°-156° C., after recrystallization from methanol-diethylether.

In the same manner but replacing1-{[2-chloro-3-(1-naphthyloxy)]propyl}piperidine with another compoundof formula 4, described in Example 2 and using the appropriate alcoholof formula R⁵ OH, other corresponding compounds of formula 1 in which R¹is lower alkyl is obtained. For instance, replacement with

1-{[2-chloro-3-(1-naphthyloxy)]propyl}pyrrolidine,

1-{[2-chloro-3-(1-naphthyloxy)]propyl}morpholine,

1-{[2-chloro-3-(1-naphthyloxy)]propyl}-4-methylpiperazine,

1-[(2-chloro-3-phenoxy)propyl]pyrrolidine,

1-[(2-chloro-3-phenoxy)propyl]piperidine,

1-[(2-chloro-3-phenoxy)propyl]morpholine, or

1-[(2-chloro-3-phenoxy)propyl]-4-methylpiperazine, and using ethanol asthe alcohol of formula R⁵ OH, gives

1-{[1-(ethoxymethyl)-2-(1-naphthyloxy)]ethyl}pyrrolidine, γ_(max)^(CHCl) 3 1595, 1580, 1460, 1245 and 1270 cm⁻¹, the correspondinghydrochloric acid addition salt of the latter compound has mp 168°-170°C.,

1-{[1-(ethoxymethyl)-2-(1-naphthyloxy)]ethyl}morpholine,

1-{[1-(ethoxymethyl)-2-(1-naphthyloxy)]ethyl}-4-methylpiperazine,γ_(max) ^(CHCl) 3 1595, 1580, 1460, 1238 and 1270 cm⁻¹, thecorresponding hydrochloric acid addition salt (dihydrochloride) of thelatter compound has mp 160°-165° C.

1-{[1-(ethoxymethyl)-2-phenoxy]ethyl}pyrrolidine,

1-{[1-(ethoxymethyl)-2-phenoxy]ethyl}piperidine, γ_(max) ^(CHCl) 3 1595,1577, 1450 and 1220 cm⁻¹, the corresponding hydrochloric acid additionsalt of the latter compound has mp 85°-90° C.,

1-{[1-(ethoxymethyl)-2-phenoxy]ethyl}morpholine, or

1-{[1-(ethoxymethyl)-2-phenoxy]ethyl}-4-methylpiperazine, respectively.

Furthermore, in the same manner and using the appropriate compound offormula 4 and benzyl alcohol as the alcohol, corresponding benzyl ethersare obtained. For example,1-{[2-chloro-3-(1-naphthyloxy)]propyl}piperidine and benzyl alcoholgives 1-{[2-(1-naphthyloxy)-1-(phenylmethoxymethyl)]ethyl}piperidine,the hydrochloric acid addition salt of the latter compound has mp145°-148° C., after recrystallization from methanol and ether.

1-{[2-chloro-3-(1-naphthyloxy)]propyl}morpholine and benzyl alcohol give1-{[2-(1-naphthloxy)-1-(phenylmethoxymethyl)]ethyl}morpholine, thehydrochloric acid addition salt of the latter compound has mp 130°-145°C., after recrystallization from methanol and ether.

1-[(2-chloro-3-phenoxy)propyl]piperidine and benzyl alcohol give1-{[2-phenoxy-1-(phenylmethoxymethyl)]ethyl}piperidine, the hydrochloricacid addition salt of the latter compound has mp 86°-93° C., afterrecrystallization from isopropanol and diethyl ether.

We claim:
 1. A compound of the formula 1 ##STR4## in which Ar is1-naphthyl, R¹ is lower alkyl containing from one to six carbon atoms ina straight chain and three to four carbon atoms in a branched chain; andR² and R³ together with the nitrogen atom to which they are joined froma heterocyclic amine radical selected from the group consisting of1-pyrrolidinyl and piperidino; or a therapeutically acceptable acidaddition salt thereof. 2.1-{[1-(Ethoxymethyl)-2-(1-naphthyloxy)]ethyl}piperidine, as claimed inclaim
 1. 3. 1-{[1-(Ethoxymethyl)-2-(1-naphthyloxy)]ethyl}piperidinehydrochloride, as claimed in claim
 1. 4.1-{[1-(Ethoxymethyl)-2-(1-naphthyloxy)]ethyl}pyrrolidine, as claimed inclaim
 1. 5. 1-{[1-(Ethoxymethyl)-2-(1-naphthyloxy)]ethyl}pyrrolidinehydrochloride, as claimed in claim
 1. 6. A pharmaceutical compositionhaving antidepressant activity comprising a compound of formula 1 ofclaim 1, or a therapeutically acceptable acid addition salt thereof at adosage from about 0.1 mg. to about 100 mg/kg per day, and apharmaceutically acceptable carrier.
 7. A method of alleviating symptomsof depression in a mammal comprising administering to said mammal aneffective dose from about 0.1 mg. to about 100 mg. per kilogram per dayof a compound of formula 1 to claim 1, or a therapeutically acceptableacid addition salt thereof.